The human nervous system is made up of an astonishing diversity of neurons. And yet only a very small number of proteins are needed to generate and determine the identity of these billions of neurons. An even smaller number of proteins, called proneural proteins, initiate and regulate neurogenesis, the manufacture of functional neurons from neural stem cells. These proneural proteins are transcription factors, meaning they control the expression of other proteins.

They are expressed very transiently during early neurogenesis. A key aspect of this system that remains to be elucidated is the precise temporal regulation of the activity of proneural proteins and the manner in which this regulation contributes to neural differentiation. Now, a study from researchers at VIB/KU Leuven has identified a previously unknown mechanism which regulates neurogenesis through precise temporal control of proneural proteins and is highly conserved between species. The team state that this mechanism, a simple reversible chemical modification, is critical for the production of a sufficient number of neurons, their differentiation as well as the development of the nervous system. The opensource study is published in the journal Cell.

Previous studies in Drosophila and in mice have shown that the expression of proneural proteins begins at very low levels in neural stem cells, thereafter increasing by self-activation; this sudden increase stops very quickly. The activity of proneural proteins thus has two characteristics, namely, significant amplitude due to auto-activation, and the other characteristic, limited duration. However, it is still unclear how a protein that auto-activates its own expression, disappears at the peak of that expression. Recent studies state that this suggests the existence of an unknown mechanism that overrides the auto-activation and synchronises the amplitude and duration of proneural protein expression. The current study investigates the control and the mechanism of proneural protein expression during retinal development in Drosophila.

The current study identifies a binary ‘all-or-nothing’ mechanism that can inactivate proneural proteins. Results show a reversible chemical modification, specifically phosphorylation, in a part of the protein that is highly conserved from fruit flies-to-mice-to-humans. Data findings show that it is this mechanism which enables the establishment of a network of functional neurons.

Results show that the suppression of this phosphorylation alters the activity of proneural proteins, causing changes in the expression of target genes, which prevents normal brain development. Data findings show that these changes interfere with signaling between neurons and have a negative impact on their number and diversity. The group note that the inhibition of this ‘all-or-nothing’ mechanism produces quantitative changes in the expression of target genes. They go on to conclude that the delicate and precise temporal control of neurogenesis is seemingly regulated by the balance of quantities of active and inactive proneural proteins.

The team surmise that their results, confirmed in another experimental model, reveal the existence of a mechanism that is both highly conserved between species and universal, which regulates neurogenesis and the generation of a sufficient and diverse number of neurons during brain development. For the future, the researchers state that throughout their lives, adults generate new neurons that help maintain all their cognitive abilities and play a key role in memory. They go on to add that understanding the role of this mechanism during neurogenesis in adults would open up a promising pathway in the fight against degenerative diseases.